PROJECT SUMMARY Our analyses from the ACTIVE study showed that one type of targeted cognitive training (CT) reduced risk of dementia by up to 48% across 10 years. While these results are encouraging, evidence is inconclusive to rec- ommend CT for dementia prevention. Many efficacious CT techniques now exist, but have distinct cognitive effects. Given that cognitive deficits are varied among those at risk for dementia, a combination of CT tech- niques may be most efficacious. Emerging evidence indicates that combining CT techniques can either en- hance or attenuate cognitive gains. However, no studies have been designed to determine the most efficacious CT combinations. Furthermore, no studies have been designed to examine the longitudinal effects of CT on dementia diagnoses. We will engage international experts in CT, mild cognitive impairment (MCI)/dementia, recruitment and retention, neuropsychological assessment, neuroimaging, biomarkers, and adaptive trial de- sign to plan and pilot test an adaptive randomized clinical trial (RCT). The RCT will determine the most effica- cious combinations of CT exercises to attenuate functional decline and delay dementia among older adults at risk due to MCI. We will first develop an effective recruitment plan of community engagement to include those often under-represented in clinical research and enroll a sample representative of the US older adult popula- tion with regard to sex, ethnicity, race, and education. In phase I a pilot trial will be conducted to refine the re- cruitment and retention plan, establish feasibility and finalize procedures, and examine the potential efficacy of 4 CT arms relative to an active control. We will apply improved methodology by comparing the CT arms to a stringent active control condition of cognitive stimulation with equivalent participant expectations and social in- teraction. Measures will include innovative indices of instrumental activities of daily living (IADL), standard cog- nitive assessments, as well as neuroimaging and blood-based biomarkers. Potential moderators of CT will also be assessed. The phase I pilot data will inform statistical simulations to design a seamless phase II/III adaptive RCT. We will simulate participant accrual and several treatment scenarios. For each scenario, we will deter- mine statistical power and sample size required for trial success. The results of these statistical simulations will be applied to optimize design and power for the phase II/III adaptive RCT. The resulting RCT will be innova- tive, in our opinion, in the application of adaptive trial methodology to efficiently identify the most efficacious combinations of CT exercises to delay dementia onset. We will plan the first trial to compare combinations of CT exercises on conversion to dementia among persons with MCI. We will document CT-related changes in the brain with neuroimaging and explore blood-based biomarkers as potential intermediary outcomes of CT. The long term goal is to apply the best CT techniques to delay dementia onset, thereby promoting public health. The contributions will be significant, advancing our understanding of how CT may be implemented to curb dementia prevalence.